Quinoline compounds and process of making same



a... July 5, 949

um'nzo T sures PATENT orncs omNoLma ci 'nglgl izs w raocsss or Joseph H. Burekhalter, Detroit, Eldon bl. Jones and Albert L. Rawlins, Grosse Pointe Woods, Frank H. Tendick, Grosse Pointe Park, and Walter F. Holcomb, Detroit, Mich, asaignorl to Parke, Davis a Company, Detroit, Mich a corporation of Michigan No Drawing.

16 Claims.

1 This invention relates to certain new and usef quinoline compounds and to methods for obtain- .ing the same. More particularly, the invention relates 'to quinoline compounds having the formula,

I OH R1 a T...

TR Ra when Z is hydrogen, halogen, CN, -COOH, --COO(lower alkyl),-C-H, lower alkyl or lower alkoxy, n being 1, 2 or 3, R is hydrogen, halogen, -OH, lower alkylene or lower alkyl, R1 and R: are the same or different alkyl radicals containing 5 to 10 carbon atoms inclusive.

These new compounds are useful therapeutic agents and, in general, they are characterized by their toxicity to plasmodiap These compounds may be used either in the form of their bases or their salts with organic or inorganic acids such as hydrochloric acid, sulfuric acid, phosphoricwith a i-haloquinoline compound of the iormula,

Application November 5, 1945, Serial No. 826,907

2 where Z, n, R, R1 and Re have the same significance as given above and x is a chlorine or bromine atom.

The reaction may be carried out by reacting approximately equimolar quantities of the 4-haloquinoline and the substituted aminophenol in a suitable solvent. Such solvents are, in general, water, water-miscible organic solvents and mixtures of water and water-miscible organic solvents. Some of the water-miscible solvents which we may use are low molecular weight alcohols such as methanol, ethanol and n-propano1,- low molecular weight ketones such as acetone and methyl ethyl ketone, and ethers such as dioxane and ethylene glycol monethyl ether.

We prefer to carry out the above reaction in the presence of an acidic catalyst; Such catalysts are dilute and concentrated organic acids, phenols and dilute inorganic acids. Some of the organic acids which we may use are acetic, propionic, butyric and the like acids. When the reaction is carried out in the presence of a concentrated organic acid or a phenol, the acid or phenol serves both as the catalyst and as the solvent. Some of the phenols which we may employ to effect the reaction are phenol, o-cresol, p-cresol, mixed cresols and the like. The inorganic acids which weuse are, in general, mineral acids such as hydrochloric, hydrobromic, sulfuric, phosphoric and like acids.

A modification of our process for obtaining these new compounds involves the use of an N-acyl derivative of the substituted aminophenol. In this modification the acyl derivative is hydrolyzed to the aromatic amine under acidic conditions and the amine so formed caused to react simultaneously or subsequently with the 4-haloquinoline compound. This is illustrated by the following two equations employing the acetyl derivative of the substituted aminophenol.

R1 CHaC Rl+ hm CHl when .z. n, R. R1. R1 and x have the significance as given above.

The invention is illustrated by the following examples. a

Example 1.-4- (3'-di-n-cmylammomethyl-4'4wdroruanilino) -7-chloroquinoline Nil-Q03 nmwmcmcmomcm Example 2.4- (3'di-n-hezylaminomethul-4'--hvdroxyanilinMJ-chloroquinoline 7 C :N(CHaCHrOHaCH|CHsC e)i 86.5 g. 2-di-n-hexylaminomethyl-4-acetylaminophenol is heated with 200 cc. oi 6 N hydrochloric acid for two hours, diluted with 150 cc. of water and the solution made Just acid to Congo red by the addition of sodium hydroxide solution.

20.8 g. of 4,7-dichl6roquinoline is added and the mixture refluxed for two hours. The mixture is cooled, made alkaline with sodium hydroxideand extracted with ether. The ether extract is washed and evaporated to dryness. The residue is taken up in hot dilute ethanol, charcoaled, flltered and the filtrate cooled. The free base which crystallizes is purified by recrystallization from either methanol or ethyl acetate-digroin mixture; M. P. 137-8" 0.

17.5 g. of the free base of 4-(3'-di-n-hexylaminomethyl-4'-hydroxyanilino) 7 chloroquinoline is taken up in alcoholic hydrogen chloride and the solution diluted with acetoner- The crystalline dihydrochloride which separates is purified by recrystallization from ethanol-acetone mixture; M. P. 220' C.

The oily dihydrochloride Example 3.--4-(3'di-n-heptylaminomethyl4-hydroxyanilmo) -7-chloroqui noline 45 'g. of 2-dl-n-heptylaminomethyl-4-acetylaminophenol is refluxed with 200 cc. of 6 N hydromixture refluxed for two hours. After cooling.

the solution is made alkaline with sodium hydroxide solution and extracted with ether. The ether is added and the 20 g. of the free base is suspended in methanol and converted to the dihydrochloride by treat-" ment with alcoholic hydrogen chloride. The product is precipitated with acetone and purified by recrystallization from methanol-acetone mixture: M. P. 202-3 0.

Example 4.-4- (3'-di-n-octylaminomethul-l'-hydroruanilino) -7-chloroquinoline 1m on mmcmcmcmomomcmcmcm)a 45 g. of 2-di-n-octylaminomethyl-i-acetylaminophenol is refluxed for one hour with 200 cc. of I ethanol and 200 cc. of 6 N hydrochloric acid. 22

g. of 4,7-dichloroquinoline dissolved in cc. of ethanol is added and the mixture refluxed for two hours. The reaction mixture is evaporated to Ldryness, treated with an excess of dilute sodium hydroxide solution and the mixture extracted with ether. The ether extracts are washed, dried and the ether distilled. The residue is taken up in alcoholic hydrogen chloride, the dihydrochlorideof the product precipitated with acetone and purifled by recrystallization from alcohol-acetone mixture; M. P.'193-5 C. 7

The base is prepared by stirring 11.5 g. of the dihydrochloride with 309 cc. of water and adding an excess of dilute sodium hydroxide solution.

The base is extracted with ether, the extracts dried and the ether distilled. The crude free base is purified by recrystallization i'rom lizroin or from methanol M. P. 128-9" C.

Example 5.3-methyl 4 -(3', -di-n-hea:ylaminomethyl-4'-hydroa:yanilino-7-chloroquinoline NHQO'H v cm mmomomcmcmomcm 40 g. of 2-di-n-hexylaminomethyl-4-acetylaminophenol is refluxed for one hour with 200 cc. of ethanol and 200 cc. of 6 N hydrochloric acid, cooled and the pH of the solution adjusted to 4 by the addition of dilute sodium hydroxide solition. 24.3 g. of 3-methyl-4,7-dichloroquinoline mixture refluxed forthree hours. The solution is cooled, made alkaline with sodium hydroxide solution and extracted with ether. Theether extract is washed with water,

dried and ether evaporated. The residue is taken up in absolute alcohol and an excess of dry hydroxenchloride in absolute alcohol added. The dihydrochloride salt is precipitated by the addition of acetone. The crude product is collected and purified by recrystallization from methanolacetone mixture.

Example 6.4 -(3'di-n-amulaminomethyl-4'Jaw droxyamlmo) -6-metho:ryquinoline CHIO it'ed by the addition sodium hydroxide soluion. added and the resultant mixture refluxed for two hours. The mixture is cooled, made alkaline with sodium hydroxide solution and extracted with ether. The ether extract is dried and then an mixture is extracted with chloroform, the chloroform extracts dried and the chloroform distilled oil. The residue is taken up in methanol and an excess of dry hydrogen chloride gas passed through the solution. The hydrochloride is preeipitated by the addition of acetone, collected and purified by recrystallization from methanolacetone mixture.

Example 7.4'-(3' di 5" methulherylaminomethyl-4'-hudroxyanilino) 6,7-dimethulquinoline (PH: culmcmcmcmomucnm 40 g. of 2-di-5'-methylhexyiaminomethyl-4- acetylaminophenol is refluxed with 200 cc. of 6N hydrochloric acid and .200 cc. of ethanol for one hour. The pH of the solution is adjusted to about 4 by the addition of sodium hydroxide solution and 21.9 g. of 4-chioro-6fi-dimethylquinoline is added. The reaction mixture is refluxed for two hours. cooled and made alkaline with sodium hydroxide solution. The oily product ,whichseparates is extracted with ether and the ether extract dried. The ether is removed by distillation and the residue taken up in alcoholic hydrogen chloride solution. The dihydro chloride salt is precipitated by the addition of acetone, collected and purified by recrystallization from methanol.

Example 8.4- (2'- hydrozyi'-di-n-amulaminontetMl-W-chloroanilino) -7-brom0quinoline on cmmcmcmomomcnm Br N 85' g. of 2-di-n-amylaminomethyl-4-chloro-6- acetylaminophenol is refluxed for one hour with 150 cc. of 8 N hydrochloric acid and 200 cc. of ethanol. The solution is made Just acid to Congo excess of dry hydrosen chloride as bubbled into the solution. The dihydrochloride which precipitates is removed by filtration and purified by recrystallization from methanol-acetone mixture.

Example 9.4-(2'- bromo 4'- di-n-amulaminomethyl-S' hudroxyanilino) -7-cwanoqzdnollne NH CH1N(CHICHCHICHIGHI)I Example 10.4- (3'-di-n amulaminomethyl-4'- hudroxu-S'mllulanilino) 5 8- methoxyquinoline CHsCH=CH1 CH: 40 g. of 2-di-n-amylaminornethyl-4-acetylarnino-6-ailylphenol is refluxed with 200 cc. of 6 N hydrochloric acid for two hours, diluted with 200 cc. of water. and the solution made just acid to Congo red by the addition of sodium hydroxide solution. 25.4 g.,of 4,5-dichloro-8-methoxyquinoline is added and the mixture refluxed for two hours. After cooling, the solution is made alkaline with sodium hydroxide and extracted with ether. The ether extracts arewashed with dilute sodium hydroxide solution, then with water and dried. The ether is evaporated and the residue, which consists of the crude free base, purified by recrystallization from either methanol or ethyl acetate-ligroin mixture.

Example 11 .-3-carbethozu 4(3' dt n amylaminomethul-4'- hydroxyanilino) 6- methamquinoline NnQ-on s a aCH:CH|C |)a cmo COOCIHI 24 g. of Q-chloro-l-bromdquinoline is.

for two hours. Acetone is added, the precipitated dihydrochloride removed by filtration and purified by recrystallization from absolute ethanol;

The intermediate aminomethylaminophenois are-usually prepared from acylaniinophenois by means of the Mannich reaction, (Organic Reactions, John Wiley and Sons, Inc., New York, 1942, vol. 1, page 303). This particular application of the reaction consists in the condensation of secondary amines with formaldehyde and] acylaminophenols having at least one unsubstituted position ortho or para to the phenolic hydroxyl. The resulting N-substituted aminomethyl acylaminophenols are hydrolyzed with mineral acid to the corresponding aminomethyl aminophenols. The same intermediates can be prepared by catalytic or nascent hydrogen reduction of aminothe formula,

methyl nitrophenols, also obtained by means oi the Mannich reaction.

The 4-haloquinolines used as starting materials can be prepared by the method of Magidson and Rubstov [.l. Geri. Chem. (U.S.S.R.), 7, 1896 1937); C. A.; 32, 564 (1938)] or from the corretions Serial No. 556,496, filed Sept. 29, 1944;

Serial No. 576,900, filed Feb. 8, 1945; Serial No. 626,908, filed Nov. 5, 1945; and Serial No. 722,474, filed Jan. 16, 1947. Attention is also directed to our copending application Serial No. 626,906.

filed Nov. 5, 1945, wherein certain quinoline compounds falling within the scope of the instant claims are claimed and an alternative process for preparing the compounds of the instant case.

is described and claimed.

What we claim .as our invention is: 1. A compound of the class consisting of a free base and its acid addition salts, said free base having the formula,

on T x where Z is a member of the class consisting of hydrogen, halogen, -CN, C0O(lower alkyl), lower alkyl and lower alkoxy, n is one of the integers consisting of 1 and 2, R is a member of the class consisting of hydrogen, halogen and lower alkenyl radicals and R1 and R2 are members of the class consisting of alkyl radicals containing 5 to 10 carbon atoms inclusive, the

- -cnm group being attached to the aryl nucleus in one of the positions ortho and para to the hydroxyl group.

I a I. An acidgaddition salt of a the formula,

mrQ-on mmomomomcmom),

-3.1An acid addition salt compound having ran-Q01: mmomomomomcmom 4. An acid addition salt of a compound having the formula,

NHQOH 7 CH] HsN(CHaCH CH1CHlCH|CHt)s 5. A compound of the formula,

6. A compound of the formula, I

. 3H0] Cl 7. A compound of the formula,

. '8. Process for obtaining a compound of the formula.

1 0H m TCHIN/ Rs which comprises reacting a 4-haloquinoline compound of the formula,

of 'a compound having halogen, -CN, --C(lower alkyl), lower alkyl 55 mesa 9 0 with a substituted aminophenol oi the formula, of the positions ortho and para to the hydroxyl group.

-011 R1 10. Process for obtaining a compound of the cnm formula,

I R, 8 J 1 11! on m:

' mmomc momcmcm where X is a member of the class consisting of chlorine and bromine, Z is a member of the class 10 consisting of hydrogen, halogen, -CN, --C0O N (lower a1 1), lower 1 and lower alkox n is one f z t g o! 1 and 2, a is a which comprises reacting 4,7-dichloroquinoline member of the class consisting of hydrogen, halowith z'min'amylamimmethyl) '4'ammopheml gen and lower alkenyl radicals and R1 and R2 are in the Presence of a mute mineral acid. members of the class consisting of alkyl radicals Pmcess for taming compound the containing 5 to 10 carbon atoms inclusive, the n i NE on m/ Q \B. H2N(CHlCHI Hl l l l)l group being attached to the aryl nucleus in one c1 of the positions ortho and para tojthe hydroxyl N F0111 Process for obtaining a compound of the which comprises reacting 4,7-dichloroquinoline form la with 2-di-n-hexylaminomethyl)-4-aminophenol l in the presence of a dilute mineral acid. I OH 12. Process for obtaining a compound of the NH, B a, formula.

L cm1 so NE on R:

CH: HQN (CHICHICHCHCHCH)! z.

01 as g which comprises reacting a '4-haloquinoline comwhich comprises reacting 3-methy1-4,7-dichlopound or the formula, roquinoline with z-(di-n-hexylaminomethyl) x 4-aminophenol in the presence of a dilute mineral acid. r 13. A hydrohalide salt of 4-[3'-di-n-amylamiz. nomethyl-4'-hydroxyanilinol 7 chloroquine line.

N/ 14. A hydrohalide salt 0! 4-[3'-di-n-hexylamiwith a substituted aminophenol of the formula. nmngthyl-f-hydroxygnflmo] 7 chlqroqujno line r 15. A hydrohalide salt of 3-methyl-4-[3'-di-na R; hexylaminomethyl- -hydroxyanilinolfl chlo I CH'N/ roquinoline. T p m JOSEPH H. mmcxnsn'rm a UJDON M. JONES.

in the presence ot'acid, where x is a member or BERT the class consisting of chlorine and bromine, Z W WICK- is a member of the class consisting of hydrogen, 'WALTER 30130353- and lower alkoxy, n is one of the integers consist- REFERENCES CITED ing of 1 and 2, R is a member of the class consist- The following references are of record in the ing or hydrogen, halogen and lower 1gilhenyl radiflle of this patent: cals and Brand Re are members or e class 0011- UNITED sisting oi allwl radicals containing 5 to 10 carbon slum PAW atoms inclusive, the mlmbel NW9 Date 1;, 1,801,980 Hermann Dec. 27, 1932 1,890,481 lluth Feb. '1, 193a \R 1,002,103 Behonhoter Mar. 21, 193:

groupbeingattaehedtothearflnaeleusinone 

